Correlation Between Erectile Dysfunction and Dose to Penile Bulb and Neurovascular Bundles Following Prostate Brachytherapy

Proceedings of the 49th Annual ASTRO Meeting that a simultaneous boost would have less toxicity than a sequential boost for prostate cancer. This study reports the acute toxicity from treating patients with high-risk prostate cancer, using whole pelvic and hypofractionated prostate RT using the Simultaneous Integrated Boost technique. Materials/Methods: Thirty patients with prostate cancer treated using this technique at our institution since July 2005 were analyzed. Twenty eight of the 30 patients received neo-adjuvant and concurrent androgen deprivation. All patients underwent CT simulation, followed by contouring of the prostate, seminal vesicles (SV), rectum, urinary bladder and pelvic lymphatics. Planning Target Volume (PTV) for prostate was generated by adding a 7 mm margin around the gross tumor volume except posteriorly, where the margin was 4 mm. The dose prescription to the pelvic lymphatics was 50.4 Gy in 28 fractions at 1.8 Gy per fraction. Simultaneously, the SV (in 8 patients) and prostate were given 56 Gy at 2 Gy per fraction and 70 Gy at 2.5 Gy per fraction respectively, by integrated boost technique. One patient received 70 Gy to the proximal SV. IMRT was given on a Tomotherapy machine, with daily MV-CT image guidance, for a median duration of 42 days. Toxicity was scored prospectively during RT using the common toxicity criteria (version 3.0). Patients were followed clinically at months 1, 3 and 6 after completion of RT and at 6-monthly intervals thereafter. The median duration of follow up is 3 months (1–14 months). Results: The mean initial PSA was 19.4 ng/ml (2.1 to 73). The Gleason score was 10, 9, 8, 7 and 6 in 1, 4, 6, 8 and 11 patients respectively. The mean PTV volumes for prostate and pelvic lymphatics were 104.6 and 482.7 cc respectively. The mean doses to 100% and 95% of the prostate PTV were 63.0 (± 3.2) and 69.2 Gy (± 1.2) respectively. The maximum dose to 1 cc of the prostate was 75.6 Gy (±1.6). The mean V70, V60 and V50 values for rectum were 2.7, 11.1 and 28.8 cc respectively. The mean dose to the ‘‘hottest 1 cc’’ of the rectum was 71.04 Gy (± 2.8). For the bladder the mean V70, V60 and V50 values were 10.7, 26.1 and 50.0 cc respectively, and the mean dose to the ‘‘hottest 1 cc’’ was 73.8 Gy (± 19.4). Over 70% of rectal and bladder toxicities were recorded by week 4 of RT. The maximum rectal toxicity was recorded as grade 1 in 16 and grade 2 in 9 patients. Five patients recorded no acute rectal toxicity. All rectal toxicities were recorded by week 5 of RT. The maximum toxicity to the bladder was grade 1 in 8 patients and grade 2 in 16. Six patients recorded no acute urinary toxicity. In all but 1 patient, the maximum bladder toxicities were recorded by week 5 of RT. There was no grade 3 or 4 rectal or bladder toxicity. Among 20 patients who were followed up for 3 or more months after RT, 18 recorded no rectal toxicity and 13 recorded no bladder toxicity at 3 months following RT. Conclusions: Whole pelvic and hypofractionated prostate RT using Simultaneous Integrated Boost is clinically feasible and is associated with modest acute rectal and bladder toxicities. Patients are being observed for possible late toxicity. Author Disclosure: R. Jacob, None; R. Nordal, None; H. Smith, None; R.Y. Kim, None; R.A. Popple, None; J.B. Fiveash, None.

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Protecting the Rectum During Prostate Cancer Irradiation: A Development of a Degradable Implanted Device

R. Ben-yosef1, A. Paz2, Y. Levy3, Y. Muchner4, S. Shohat4, B. Corn5, A. Vexler5, A. Domb3 1 Ichilov Medical Center and Tel-Aviv University School of Medicine, Tel-Aviv, Israel, 2Barzilai Medical Center, Ashkelon, Israel, 3Hebrew University, Jerusalem, Israel, 4Bioprotect, Kiriat-Gat, Israel, 5Ichilov Medical Center, Tel-Aviv, Israel

Background: The hypofractionation and subsequent possible higher rectal dose and impotency morbidity rate evoked a need for better protection of non-treated organs in the irradiation of prostate cancer. Materials/Methods: An implantable, biodegradable inflatable triangle pre-shaped balloon (15–20 mm thickness), made of commercially used material of the Poly (L-Lactide-co-e-caprolactone) co-polymer, was developed to provide organs separation. A simple routine transperineal approach is used for the insertion and deployment of the device with a special delivery system that releases the inflated balloon between the anterior rectum and the prostate. Several in vitro and in vivo studies (including a human phantom model) studies were done. Results: The device was found to be biocompatible. Upon inflation in situ, the balloon separates the tissues located on both its sides. A human phantom model demonstrated an easy position of the balloon in the tissue between the prostate and the anterior rectum using a perineal approach. In-vitro and in-vivo tests showed that the device kept inflated for several months and then completely biodegraded, with no systemic or local toxicity as shown by histopathology and blood tests from rabbits, dog (up to 1 year) and pigs. A long follow-up (up to 10 months) of the irradiated pigs (15 Gy in 3 fractions, one week apart) showed stable balloon position with no local or systemic side effects that biodegraded as expected. Retrospective human XRT plans for prostate cancer, calculating at a 15 mm separation from the rectum, showed a 35–50% reduction in radiation dose to the anterior rectum. Conclusions: This novel device was safe and effective for its intended use to separate between tissues for a desired duration of time. A clinical study will commence to evaluate the safety and the efficacy of this device in the irradiation of prostate cancer patients. Author Disclosure: R. Ben-yosef, yes, F. Consultant/Advisory Board; A. Paz, yes, E. Ownership Interest; Y. Levy, None; Y. Muchner, yes, A. Employment; S. Shohat, yes, E. Ownership Interest; B. Corn, yes, F. Consultant/Advisory Board; A. Vexler, None; A. Domb, yes, E. Ownership Interest.

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Correlation Between Erectile Dysfunction and Dose to Penile Bulb and Neurovascular Bundles Following Prostate Brachytherapy

A. N. Solan, R. G. Stock, J. A. Cesaretti, N. N. Stone Mount Sinai School of Medicine, New York, NY Purpose/Objective(s): We evaluated the relationship between erectile function and dose to the penile bulb and neurovascular bundles after real-time ultrasound-guided prostate brachytherapy. Because the neurovascular bundles are difficult to define on CT imaging, we focused on dose to the fascial plane volumes that house the neurovascular bundles and postulated that higher doses to these structures would be predictive of erectile dysfunction.

S351

I. J. Radiation Oncology d Biology d Physics

S352

Volume 69, Number 3, Supplement, 2007

Materials/Methods: One hundred forty-seven patients who underwent prostate brachytherapy between January 2003 and February 2006 met the following eligibility criteria: (1) Treatment with 125I brachytherapy to a prescribed dose of 160 Gy ± hormones without supplemental external beam radiation therapy; (2) Identification as potent prior to the time of implantation based on a score $2 on the physician-assigned Mount Sinai Erectile Function Score (MSEFS) and a score $16 on the abbreviated International Index of Erectile Function patient assessment; (3) Minimum follow-up of 12 months. Median followup was 25.7 months. The penile bulb was contoured on the postimplant CT scan at 3 mm intervals, and the volume of penile bulb receiving 100% of the prescription dose (V100) and the dose to the hottest 5% of the penile bulb (D5) were recorded. The right and left neurovascular bundles and surrounding fascial planes were outlined as triangular structures bounded by the posterolateral edge of the prostate, the levator ani muscle, and the rectal wall. For each neurovascular bundle structure, the volumes receiving 100% and 150% of the prescription dose (NVB V100 and V150) were recorded. Postimplant impotence was defined as MSEFS \2. Results: The 3-year actuarial rate of impotence was 23% (34/147). An additional 43% (49/113) of potent patients were using a potency aid at last follow-up. Penile bulb V100 values ranged from 0–0.05 cc (median, 0 cc) with D5 values ranging from 12.5–97.9 Gy (median, 40.8 Gy). There was no correlation between penile bulb D5 or V100 and postimplant impotency on actuarial analysis. For the combined right and left neurovascular bundle structures, V100 values ranged from 0.3–5.1 cc (median, 1.8 cc), and V150 values ranged from 0–1.5 cc (median, 0.31). There was no association between neurovascular bundle V100 or V150 and postimplant impotency on actuarial analysis. Cox regression analysis revealed no correlation between postimplant impotency rates and age at implant, history of diabetes mellitus, degree of pretreatment potency, hormone use, left NVB V100, right NVB V100, or total NVB V100. Conclusions: Penile bulb doses are low following real-time ultrasound-guided prostate brachytherapy. There was no relationship between radiation dose to the penile bulb and the development of impotency. Doses to the neurovascular bundles also showed no correlation to postimplant impotency. Such a dose response may exist, but our implants were too consistent with respect to technique and delivered dose over the selected time period to detect such a relationship. Author Disclosure: A.N. Solan, None; R.G. Stock, CR Bard, F. Consultant/Advisory Board; J.A. Cesaretti, CR Bard, F. Consultant/Advisory Board; N.N. Stone, Prologics Inc., G. Other.

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Radiation Modulation of MicroRNA in Prostate Cancer Cells

1

S. Josson , S. Sung1, K. Lao2, L. W. K. Chung1, P. A. S. Johnstone1 1

Emory University, Atlanta, GA, 2Applied Biosystems, Foster City, CA

MicroRNAs (miRNA) are evolutionarily conserved short noncoding RNA which regulate gene expression and play an important role in response to cellular stress. The role of specific miRNA in radiation response has not been previously studied. Using highly sensitive multiplexed quantitative real-time PCR we determined the differential expression profile of 330 miRNA in androgen dependent LNCaP prostate cancer cells and androgen independent C4-2 prostate cancer cells, and their response to radiation. Several miRNAs were altered in response to radiation; the most significant effect was observed in hsa-miR-521, which disappeared in both cell lines after radiation treatment. We hypothesize that the downregulation of this miRNA may lead to the upregulation of radiation responsive genes; predictably, some of the target genes of this miRNA are genes involved in DNA repair. To determine if the decrease in hsa-miR-521 plays a functional role in response to radiation, we transiently overexpressed hsa-miR-521 mimic in LNCaP cells; radiation sensitivity was quantified using cell viability assays. Significant sensitization was observed when hsa-miR-521 was overexpressed. Hsa-miR-521 by itself was not found to be toxic to the cells, suggesting that the sensitization was specific only to radiation treatment. Therefore, hsa-miR-521 may play a crucial role in promoting radiation sensitivity of prostate cancer cells. Differential miRNA expression was also tested between normal PrEC prostate epithelial cells and the LNCaP series of cell lines, representing cancer progression. LNCaP and C-4 are androgen dependent prostate cancer cells and C4-2 and C4-2B are androgen independent prostate cancer cells, whereas C4-2B metastasizes to the bone. Some miRNA were increased in all cancers compared to normal cells and some where absent in androgen independent cells. These results suggest that differential miRNA expression, in normal prostate epithelial and cancer epithelial cells differ with stages of progression and degree of androgen-dependency. This differential miRNA expression could alter the outcome of transformation and cancer progression. Our results demonstrate for the first time a potentially important role for hsa-miR-521 in radiation sensitivity of prostate cancer cells (Table).

MicroRNA altered in radiation response in prostate cancer cells

miRNA Decreased hsa-miR-521 hsa-miR-196a hsa-miR-133b hsa-miR-487 hsa-miR-122a miRNA Increased hsa-miR-34c hsa-miR-372 hsa-miR-520c

LNCaP

LNCaP + 6 Gy Fold Change

TTEST p value

1 1 1 1 1

absent absent .387 .003 .004

.001 .001 .012 .001 .001

1 1 1

2.928 556 417

.001 .002 .011

miRNA Decreased hsa-miR-521 hsa-miR-196a hsa-miR-133b hsa-miR-143 hsa-miR-135b miRNA Increased hsa-miR-34c hsa-miR-383 hsa-miR-154*

C4-2

C4-2 + 6 Gy Fold Change

TTEST p value

1 1 1 1 1

absent .057 .1 .004 .163

.001 .001 .003 .001 .02

1 1 1

4 23 22

.001 .05 .01

Author Disclosure: S. Josson, None; S. Sung, None; K. Lao, None; L.W.K. Chung, None; P.A.S. Johnstone, None.